IL-17 links the tumor suppressor LKB1 to gastrointestinal inflammation and polyposis

Loss-of-function mutations in the tumor suppressor liver kinase B1 (LKB1) promote the development of Peutz-Jeghers Syndrome (PJS), a chronic disease characterized by the development of gastrointestinal (GI) polyps. Treatment options for patients are extremely limited due to a poor understanding of how LKB1 mutations lead to the development of GI polyps. Here, we reveal a role for CREB-regulated transcription coactivator 2 (CRTC2) signaling in the regulation of inflammatory potential in LKB1 mutant T cells. We also demonstrate that targeting CRTC2 and pathogenic T helper 17 (Th17) cells reduces GI polyp growth in LKB1 mutant mice. Our data reveal a critical role for CRTC2 in LKB1-mediated T cell inflammatory responses that we hypothesize predisposes PJS patients harboring LKB1 mutations to GI polyp development. RNA-seq was performed on GI polyp tissue from 12-month-old LKB1-mutant mice (whole-body heterozygosity for Stk11) or control stomach tissue from 12-month-old wild type mice. RNA-seq was also performed on Lkb1+/-, Lkb1+/-/Crtc2-/-, and A485-treated Lkb1+/- T cells differentiated under pathogenic Th17 conditions.